15-48463253-TAA-TAAA

Variant names:

• chr15-48463253-T-TA
• rs3833018
• NM_000138.5:c.5066-14dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000138.5(FBN1):​c.5066-14dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0165 in 1,609,614 control chromosomes in the GnomAD database, including 618 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (64 hom., cov: 33)
  • Exomes 𝑓: 0.016 (554 hom.)
• Consequence: FBN1 NM_000138.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14 O:1
• Conservation: PhyloP100: -0.716
• Publications: 1 publications found

Genes affected

FBN1 (HGNC:3603): (fibrillin 1) This gene encodes a member of the fibrillin family of proteins. The encoded preproprotein is proteolytically processed to generate two proteins including the extracellular matrix component fibrillin-1 and the protein hormone asprosin. Fibrillin-1 is an extracellular matrix glycoprotein that serves as a structural component of calcium-binding microfibrils. These microfibrils provide force-bearing structural support in elastic and nonelastic connective tissue throughout the body. Asprosin, secreted by white adipose tissue, has been shown to regulate glucose homeostasis. Mutations in this gene are associated with Marfan syndrome and the related MASS phenotype, as well as ectopia lentis syndrome, Weill-Marchesani syndrome, Shprintzen-Goldberg syndrome and neonatal progeroid syndrome. [provided by RefSeq, Apr 2016]

FBN1 Gene-Disease associations (from GenCC):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Marfan syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Orphanet, G2P, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Acromicric dysplasia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• progeroid and marfanoid aspect-lipodystrophy syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• stiff skin syndrome

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Weill-Marchesani syndrome 2, dominant

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• isolated ectopia lentis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal Marfan syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Weill-Marchesani syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ectopia lentis 1, isolated, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• Shprintzen-Goldberg syndrome

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 15-48463253-T-TA is Benign according to our data. Variant chr15-48463253-T-TA is described in ClinVar as Benign. ClinVar VariationId is 178599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000138.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	NM_000138.5	MANE Select	c.5066-14dupT		intron	N/A	NP_000129.3
	FBN1	NM_001406716.1		c.5066-14dupT		intron	N/A	NP_001393645.1	P35555

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBN1	ENST00000316623.10	TSL:1 MANE Select	c.5066-14_5066-13insT		intron	N/A	ENSP00000325527.5	P35555
	FBN1	ENST00000559133.6	TSL:1	n.5066-14_5066-13insT		intron	N/A	ENSP00000453958.2	H0YND0
	FBN1	ENST00000537463.6	TSL:5	n.*829-14_*829-13insT		intron	N/A	ENSP00000440294.2	F6U495

Frequencies

GnomAD3 genomes AF: 0.0229 AC: 3471 AN: 151366 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.0335

Gnomad ASJ AF: 0.00780

Gnomad EAS AF: 0.0835

Gnomad SAS AF: 0.0475

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00969

Gnomad OTH AF: 0.0231

GnomAD2 exomes AF: 0.0261 AC: 6549 AN: 250872 AF XY: 0.0248

Gnomad AFR exome AF: 0.0306

Gnomad AMR exome AF: 0.0517

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0764

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0252

GnomAD4 exome AF: 0.0158 AC: 23076 AN: 1458132 Hom.: 554 Cov.: 32 AF XY: 0.0162 AC XY: 11777 AN XY: 725562

African (AFR) AF: 0.0323 AC: 1079 AN: 33392

American (AMR) AF: 0.0509 AC: 2268 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 307 AN: 26056

East Asian (EAS) AF: 0.110 AC: 4349 AN: 39656

South Asian (SAS) AF: 0.0354 AC: 3050 AN: 86184

European-Finnish (FIN) AF: 0.0118 AC: 627 AN: 53342

Middle Eastern (MID) AF: 0.0230 AC: 132 AN: 5744

European-Non Finnish (NFE) AF: 0.00903 AC: 10014 AN: 1108946

Other (OTH) AF: 0.0207 AC: 1250 AN: 60268

GnomAD4 genome AF: 0.0230 AC: 3482 AN: 151482 Hom.: 64 Cov.: 33 AF XY: 0.0243 AC XY: 1798 AN XY: 73998

African (AFR) AF: 0.0323 AC: 1331 AN: 41256

American (AMR) AF: 0.0338 AC: 514 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00780 AC: 27 AN: 3462

East Asian (EAS) AF: 0.0837 AC: 430 AN: 5140

South Asian (SAS) AF: 0.0480 AC: 230 AN: 4790

European-Finnish (FIN) AF: 0.0146 AC: 153 AN: 10476

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00969 AC: 657 AN: 67828

Other (OTH) AF: 0.0228 AC: 48 AN: 2104

Alfa AF: 0.00624 Hom.: 2

Bravo AF: 0.0251

Asia WGS AF: 0.0720 AC: 252 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (4)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	2	not provided (2)
-	-	1	Acromicric dysplasia (1)
-	-	1	Ectopia lentis (1)
-	-	1	Geleophysic dysplasia (1)
-	-	1	Marfan syndrome (1)
-	-	1	Marfan syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Stiff skin syndrome (1)
-	-	1	Weill-Marchesani syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3833018; hg19: chr15-48755450;